Maintenance of cellular homeostasis under stress conditions occurs through the initiation of specific signalling mechanisms between distinct cellular compartments. Dysfunction in mitochondrial function has been recognized as one of the main etiopathological factors in Parkinson's Disease (PD) neurodegeneration and has been strongly linked with other neurodegenerative diseases. In addition, neurodegenerative diseases are critically influenced by ageing, process associated with accumulation of DNA damage. Mitochondria quality control (mtQC) signalling comprises two main aspects: 1) molecular quality control also known as mitochondrial unfolded protein response and 2) organellar quality control termed mitophagy. The mtQC signalling implicates a plethora of cellular processes including transcription factors translocations, AMPK phosphorylation and metabolic changes. We and others have shown that mitochondrial dysfunction leads to the activation of the Integrated Stress Response (ISR) signalling pathway, which occurs via the b-zip transcription factors ATF4, ATF5 and CHOP. Here we will discuss how mitochondria-nucleus communication operates via the ISR in the context of combined mitochondrial and genotoxic stress and how this mechanism contributes to intracellular and intercellular signalling of stress.